Hypofractionated high dose radiation therapy is an increasingly important treatment approach. Image guidance is imperative to ensure accurate patient positioning and to allow the use of tight treatment margin for high dose delivery. At present, the prevailing guidance method employs x- ray imaging to provide 3D volumetric and/or 2D projection information. Unfortunately, the approach is found wanting for tumors at low radiographic contrast with the surrounding tissue. These include important abdominal sites such as prostate, pancreas and liver. Consequently, detection of implanted markers has been employed as an alternative. However, these surrogates are also less than ideal due to the lack of anatomic information and the invasive nature of the procedure. In response to PAR10-169, an academic-industrial partnership is formed between Johns Hopkins University (JHU), Elekta-Resonant and Cleveland Clinic (CC), to develop an integrated 3D x-ray/ultrasound imaging system to provide on-board guidance for hypofractionated radiation therapy. The partnership has significant expertise in x-ray and ultrasound imaging, robotic engineering and radiation therapy. We have 3 specific aims. Specific Aim 1 is to design and construct the system. A 3D ultrasound imaging system will be docked onto a medical accelerator equipped with on-board x-ray cone-beam CT (CBCT) imaging. Ultrasound imaging overcomes the hurdle of detecting low contrast soft tissue target with x-ray imaging, while CBCT provides the anatomic information for setting up the patient in the machine frame of reference and for dose re-calculation if necessary. Robotic control with force sensors will be employed to automate the positioning of the ultrasound system which will remain on the patient throughout the treatment session to provide real-time monitoring. The procedure is non-invasive. The monitoring is non-ionizing and desirable for applications with pediatric patients. Specific Aim 2 focuses on optimizing the IGRT workflow for planning, radiation delivery to avoid the interference of imaging and irradiation procedures with each other. For Specific Aim 3, we will validate the performance of the integrated imaging system at JHU and CC. We will test the hypothesis that guidance using the integrated robotic system is superior to CBCT or ultrasound imaging alone by demonstrating that the target definition is more reproducible and less user-dependent. The expertise of partners is well suited to fulfill the expectations of PAR10-169. Two commercial grade systems will be constructed. JHU and CC represent the end-users to conduct in-field validation of these systems. Elekta-Resonant is also an ideal industrial partner to pursue commercialization for dissemination in the community.